Adolescence is characterized by heightened vulnerability to health risk behaviors such as experimenting with drugs and alcohol and engaging in unsafe sexual activity that together are the major proximal causes of drug addiction and sexually transmitted diseases (STDs) including human immunodeficiency virus (HIV) infection. Research in developmental neuroscience suggests that risk-taking in adolescence may derive from differing developmental trajectories of two distinct neural systems that regulate risky decisions: (i) early maturation of a reward system that biases decisions toward high-reward options, combined with (ii) late maturation of a cognitive control system that biases decisions away from options with potential negative consequences. Yet, we know very little about how developing reward and control neural systems interact to produce differential vulnerability to poor decision-making that leads to adverse health outcomes. We propose the first longitudinal analyses to examine how individual differences in developmental trajectories of reward/risk sensitivity and cognitive control are related to the development of adolescent substance use and risky sexual behaviors. We will study a sample of 120 adolescents from understudied Appalachian communities for the outcomes of substance use (e.g., tobacco, alcohol, marijuana, and other illicit drug use) and HIV/STD-related risky sexual behaviors (e.g., multiple sexual partners and unprotected sex) throughout middle adolescence (13-17 years). We will use functional magnetic resonance imaging (fMRI) to identify neural correlates of risky decision- making: reward/risk sensitivity (reward system) and cognitive control (control system). We will examine our hypotheses at the neural level as well as within the context of standard assessments of behavior (e.g., executive function tasks) and self- and parent reported attributes (e.g., approach/avoidance) to obtain a more integrated understanding of the connections between reward and control systems and adolescent risk-taking. Based on our conceptual model we will test whether cognitive control statistically moderates the effects of reward/risk sensitivity on adolescent substance use and HIV/STD-related risky sexual behaviors. We hypothesize that neural patterns of hyperactive reward sensitivity and hypoactive risk sensitivity will be related to greater involvement in substance use and risky sexual behaviors, especially for those adolescents with hypoactive cognitive control. The proposed research will make theoretical contributions by providing new knowledge about the interaction between reward and control neural systems that, to our knowledge, have not been studied. Our design will also allow us to investigate the reciprocal interplay between adolescent risky behaviors and these neural processes. The findings from this work will yield critical information for identifying adolescents with high neurobiological vulnerability for developing substance abuse and risky sexual behaviors and will have the potential to improve prevention efforts to positively alter developmental pathways of youth who are at risk for drug addiction and HIV/STDs.